AB0084 INCREASED LIVER DISEASE RISK IN RHEUMATOID ARTHRITIS IS ASSOCIATED WITH DISEASE ACTIVITY, INFLAMMATORY MARKERS, INSULIN RESISTANCE AND ACPAs. INFLUENCE OF METHOTREXATE
Authors: I. Arias de la Rosa, M. Ruiz-Ponce, L. Cuesta López, M. D. Gahete, N. Herman-Sanchez, A. Lucendo-Villarin, P. Navarro-Sanchez, M. C. Ábalos-Aguilera, C. Perez-Sanchez, R. Ortega Castro, J. Calvo Gutierrez, C. Lopez-Pedrera, A. Escudero Contreras, E. Collantes Estevez, N. Barbarroja Puerto
Journal: Annals of the Rheumatic Diseases (2022)

Background Liver alterations, especially nonalcoholic fatty liver disease (NAFLD) are associated with Rheumatoid Arthritis (RA). This abnormality appears as asymptomatic and can progress to a severe liver damage rapidly. Chronic inflammation, treatment with methotrexate (MTX) or even autoimmunity are factors that might be involved, however the mechanisms related to this comorbidity in RA are not completely stablished yet. Objectives 1) To evaluate the liver disease risk in RA patients through feasible indexes to be used in the daily clinical practice and its relationship with clinical features of the disease; 2) To analyze the impact of antibodies to citrullinated proteins antigens (ACPAs) on hepatic function; 3) To examine the influence of MTX treatment on classical parameters and new indexes of hepatic dysfunction in a cross-sectional and longitudinal cohort. Methods 1) Cross-sectional study in 307 body mass index matched subjects: 55 healthy donors (HDs), 190 RA patients and 62 non-RA patients diagnosed with NAFLD through echography. Obese patients were excluded from the study. 2) Longitudinal study with 50 RA patients treated with MTX for 6 months. Clinical and laboratory parameters, subclinical liver disease biomarkers and 4 indexes to evaluate the presence of fibrosis and steatosis (APRI, “AST to platelet ratio index”; FIB-4, “fibrosis 4 score”; HSI, “hepatic steatosis index” and TyG, “triglycerides and glucosa index”) were measured. Association studies of hepatic dysfunction with clinical parameters were performed; A panel of 15 proteins directly involved in hepatic disease was analyzed in serum (C1QTNF1, IL7R, TIE1, CCL5, REG3A, CA3, LCN2, CCL14, NRP1, ICAM3, CD59, TIMP1, CNDP1, GNLY, IGFB6). 3) In vitro experiments were carried out in hepatocyte cell line (HEPG2) treated with ACPAs. Results Using NALFD patients as positive controls for the four liver disease indexes, RA patients showed significantly higher levels of HSI and TyG biomarkers. In fact, a high proportion of these patients (42.7%) were estimated to suffer NALFD. The association studies in RA patients showed that liver disease biomarkers (HSI and TyG) were related to the insulin resistance state, inflammation, complement component 3(C3), disease activity, and the levels of ACPAs. Serum levels of CNDP1, CCL5, GNLY, TIMP-1, CD59 and CCL14 were significantly increased in RA patients and correlated with hepatic damage indexes. Treatment with ACPAs on hepatocytes promoted the secretion of C3 in parallel with a significant alteration of genes related to glucose and lipid metabolisms, inflammation, fibrosis and apoptosis. MTX treatment, from the point of cross-sectional approach, was not associated with an increase of hepatic enzymes, serum proteins nor liver disease indexes. Treatment with MTX for 6 months did not affect those levels either. Conclusion 1) A high proportion of RA patients present an alteration in markers of NAFLD, associated with insulin resistance state, disease activity, inflammation, component C3 and ACPAs levels; 2) the autoantibodies could directly impact hepatocyte biology altering the expression of genes related to glucose and lipid metabolisms, inflammation, fibrosis and apoptosis, 3) Treatment with MTX did not promote any alteration in subclinical liver disease biomarkers after 6 months of treatment. Funded by Institute of Health Carlos III (PI20/00079). Disclosure of Interests None declared